Hiccups and Other Gastrointestinal Symptoms

Nabeel Sarhill

Fade Mahmoud

Gastrointestinal (GI) symptoms are commonly seen in patients with cancer, regardless of the disease site. These symptoms are experienced during the course of the illness or as a result of therapy. However, it should be remembered that many GI problems seen in patients with cancer are also seen in those without cancer. In fact, some GI symptoms are very common, and although they cause distress, they rarely represent life-threatening pathology. This presents a problem, as patients and physicians face the concern that every new symptom is related to the cancer. This chapter focuses primarily on GI symptoms as they relate to cancer and its treatment, but the reader is reminded that most GI symptoms are not directly due to the cancer.

HICCUPS

Definition/Incidence

Hiccup is a spasmodic, involuntary contraction of the inspiratory (external) intercostal muscles and the diaphragm associated with a strong, sudden inspiration and abrupt glottic closure (1). The medical term for hiccups, singultus, is of Latin origin and means to gasp or sigh. Hiccups were first attributed to phrenic nerve irritation by Shortt in 1833 (2). Hiccups can be classified by their duration as acute (up to 48 hours), persistent or protracted (longer than 48 hours), and intractable (>1 month) (1,2).

Pathophysiology/Etiology

Hiccup is a primitive reflex that contains three parts. The afferent portion consists of branches of the vagus nerve, the phrenic nerve, and the sympathetic chain from T6 to T12. The hiccup center is located in the spinal cord between C3 and C5. The efferent limb is primarily the phrenic nerve with involvement of the efferents to the glottis and accessory muscles of respiration (1).

In addition to the neural pathways, numerous anatomic structures are involved in the mechanism of hiccup (epiglottis, larynx, hyoid muscles, superior constrictor of the pharynx, esophagus, stomach, diaphragm, and exterior intercostal, sternocleidomastoid, anterior serratus, and scalene muscles). Given this extensive list, it is not surprising that hiccup has been associated with many conditions affecting the central nervous system (CNS), thorax, mediastinum, and abdominal viscera, although a cause-and-effect relationship has not always been clear. One report listed over 100 causes, the most common being an overdistended stomach (3). Some cancer-related causes of persistent and intractable hiccups are listed in Table 17.1.

Treatment/Management

Management is usually aimed at inhibiting or interrupting the irritated reflex arc. Nonpharmacologic therapies (4) include the Valsalva maneuver (expiring forcefully against a closed glottis), ocular compression, carotid sinus massage, traction on the tongue, ice water gargles, noxious odors or tastes, breath holding, rebreathing into a paper bag, gagging, drinking from a glass while holding a pencil between the teeth or while bending over head down, taking as many sips of fluid as rapidly as possible without breathing, ingesting granulated sugar, biting a lemon wedge, or inducing emesis. Physical changes that may help stop hiccups include pulling the knees to chest, leaning forward to compress the chest, tapping over the fifth cervical vertebra, or applying ice over the phrenic nerve. Although these measures have not been subjected to controlled clinical trials, most are worth a try. However, many are not practical for these patients, who may be too debilitated to tolerate even simple maneuvers (e.g., holding breath).

Acupuncture may be a clinically useful, safe, and lowcost therapy for persistent hiccups in patients with cancer. In a recent retrospective case series, 16 adult male patients aged 27 to 71 with persistent cancer-related hiccups received one to three acupuncture sessions over a 1- to 7-day period. Thirteen patients experienced complete remission of persistent hiccups (p < 0.0001) and three patients experienced decreased hiccups severity. Significant improvement was observed in discomfort (p < 0.0001), distress (p < 0.0001), and fatigue (p = 0.0078) (5).

Many drugs have been used to treat hiccups (Table 17.2). The literature is largely based on case reports and no definitive clinical evidence is available to define the standard treatment. The only medication approved by the US Food and Drug Administration for hiccups is the antipsychotic phenothiazine chlorpromazine (25 to 50 mg through i.v., orally, or rectally three to four times a day) (6). Chlorpromazine is less attractive in patients with cancer due to side effects of hypotension and sedation. Other medical therapies include haloperidol (1 to 5 mg orally three times daily or subcutaneously every 12 hours) (7), nifedipine (10 mg p.o. three times daily) (8), metoclopramide (10 mg p.o. or i.v. every 6 hours) (9), and baclofen (10 to 20 mg p.o. three times a day) (10).
Baclofen should be given with caution to the elderly due to frequent side effects of sedation, insomnia, dizziness, weakness, ataxia, and confusion (10). If hiccups persist, amitriptyline (10 mg three times a day) (11), carbamazepine (200 mg three times a day) (12), diphenylhydantoin (200 mg i.v. and then 100 mg p.o. four times a day) (13), or valproic acid (15 mg/kg/d in divided doses) (14) can be administered. Midazolam has been successfully utilized in patients with terminal hiccups (15). Midazolam infusion may be especially useful if intractable hiccups occur in the setting of refractory terminal delirium or agitation.

TABLE 17.1 Causes of hiccups in the patient with cancer

Uremia

Alcohol

Hyponatremia, hypokalemia, and hypocalcemia

Fever

Diaphragmatic irritation (diaphragmatic tumors and pericarditis)

Pleuritis

Esophageal obstruction

Pericarditis

Hepatomegaly

Subphrenic abscess

Esophageal cancer

Mediastinal tumors

Herpes zoster

Lung cancer

Gastric distension

Gastric cancer

Pancreatic cancer

Intra-abdominal abscess

Bowel obstruction

Gastrointestinal hemorrhage

Short-acting barbiturates

Dexamethasone

Diazepam and chlordiazepoxide

Infections (meningitis)

Grief reaction

Psychosis

A comprehensive list of the causes of hiccups can be found in Launois S, Bizec JL, Whitelaw WA, et al. Hiccup in adults: an overview. Eur Respir J. 1993;6:563-575.

Gabapentin, an anticonvulsant, produces blockade of neural calcium channels and increases release of γ-aminobutyric acid (GABA), which may modulate diaphragmatic excitability. Case series have shown gabapentin

(300 mg p.o. three times daily with dose titration) to be effective in intractable hiccups (16). In a retrospective study, 37 (3.9%) of 944 in-hospital patients and 6 (4.5%) of 134 patients observed at home presented with severe chronic hiccups. Gabapentin (300 mg three times a day with dose titration) was effective in these cases. Responses were observed in 32 patients (74.4%) with gabapentin at a dosage of 900 mg/d and in 9 patients (20.93%) at a dosage of 1,200 mg/d (17). Gabapentin is not hepatically metabolized and has a relatively safe side-effect profile making it a potentially useful agent in the advanced cancer setting, especially among patients requiring adjuvant analgesia due to neuropathic cancer pain (18,19). Nebulized lidocaine maybe effective via a local anesthetic effect upon irritant sensory afferents and has a much greater safety profile than does the intravenous

route (20). Similarly, nebulized saline solution has been reported by some authors to terminate hiccups in the palliative care setting (21). Efficacy has been claimed for a variety of drugs that have a peripheral action such as atropine, edrophonium, procainamide, and quinidine. Methylphenidate (10 mg p.o. daily) is reported to be effective in the treatment of hiccups (22).

TABLE 17.2 Commonly used drugs in the treatment of hiccups

Drug	Dose	Side Effects
Chlorpromazine	25-50 mg i.v. three to four times daily, infused slowly 25-50 mg p.o. three times daily	Sedation, hypotension, and extrapyramidal symptoms
Metoclopramide	10 mg p.o. or i.v. three to four times daily	Extrapyramidal symptoms^a
Gabapentin	300 mg p.o. three times daily	Drowsiness, headache, fatigue, blurred vision, tremor, anxiety, skin rash, itching, fever, flu-like symptoms, and seizures
Haloperidol	1-5 mg p.o. three times daily or s.c. q12h	Sedation and extrapyramidal symptoms
Baclofen	10-20 mg p.o. three times daily	Sedation, confusion, and less commonly, nausea and fatigue
Nifedipine	10 mg p.o. three times daily	Hypotension, use with caution in patients with coronary artery disease
Amitriptyline	10 mg p.o. three times daily	Cardiac arrhythmias, blurred vision, urinary retention, dry mouth, constipation, and dizziness
Carbamazepine	200 mg three times daily	Dizziness, drowsiness, nausea or vomiting, and low red and white blood cell counts
Diphenylhydantoin	200 mg i.v. once and then 100 mg p.o. four times daily	Enlarged gums, unsteadiness, confusion, lymphadenopathy, fever, muscle pain, skin rash or itching, slurred speech, sore throat, and nervousness or irritability
Valproic acid	15 mg/kg p.o. daily in one to three divided doses	Dizziness, drowsiness, nervousness, upset stomach, vomiting, diarrhea, tremor, sore throat, and drug-induced hepatitis
Ketamine (Ketalar)	0.4 mg/kg (one-fifth of the usual anesthetic dose) i.v.; supplemental dose of one-third to half initial dose may be given for maintenance	Resuscitative equipment should be immediately available during administration of medication
Lidocaine	1 mg/kg i.v. loading dose followed by an infusion of 2mg/min i.v.	May increase risk of adverse central nervous system and cardiac effects in elderly; high plasma concentrations can cause seizures, heart block, and atrioventricular conduction abnormalities
Ephedrine	25 mg i.m. q6h	Headache, restlessness, anxiety, tremor, weakness, dizziness, confusion, delirium, hallucinations, palpitations, sweating, nausea or vomiting, and urinary retention
		Serious side effects include severe hypertension that may lead to cerebral hemorrhage or cardiac ischemia
Methylphenidate (Ritalin)	5 mg p.o. daily or divided b.i.d.; not to exceed 60 mg/d	Insomnia, anorexia, irritability, nervousness, upset stomach, headaches, dry mouth, blurry vision, nausea, hypersensitivity, palpitations, and cardiac arrhythmias
Other therapies	Behavioral conditioning (including other members of the family unit) Hypnosis Acupuncture Phrenic nerve or diaphragmatic pacing
^aMore common in younger women.
Adapted from Liu FC, Chen CA, Yang SS, et al. Acupuncture therapy rapidly terminates intractable hiccups complicating acute myocardial infarction. South Med J. 2005;98(3):385-387; Schiff E, River Y, Oliven A, et al. Acupuncture therapy for persistent hiccups. Am J Med Sci. 2002;323(3):166-168.

Various invasive methods have been tried. As gastric distension is the most common cause of hiccups in patients with cancer, initial treatment should be aimed at relieving the distension and increasing gastric emptying. The insertion of a nasogastric tube may also serve the purpose by stimulating the pharynx or causing gagging. High-pressure oxygen inhalation has been tried. Percutaneous stimulation of the phrenic nerve has also been reported. Phrenic nerve injection may be a reasonable option for drug refractory hiccups if an experienced practitioner is available. In a case series, 1% lidocaine solution was administered via ultrasonographic guidance to the area of the phrenic nerve to five cancer patients with intractable hiccups. Hiccups ceased in all five patients within 5 minutes. Hiccups did not recur in three patients, and there were no adverse effects (23). A surgical approach consists of an attack on the phrenic nerve (by a crush technique), usually first attempted on the left. Regardless of the treatment, in most cases, hiccups stop because of, or in spite of, therapeutic measures (24,25).

It is important to remember that hiccups in cancer may be extremely distressing and affect the quality of life by interfering with food intake, causing insomnia, or exacerbating pain and other symptoms. For this reason, it may be advisable to pursue diagnosis and treatment more aggressively than in the general population (26).

DYSPEPSIA

Definition/Incidence

Dyspepsia consists of episodic or persistent symptoms that include abdominal pain or discomfort, postprandial fullness, abdominal bloating, belching, early satiety, anorexia, nausea, vomiting, heartburn, and regurgitation. There is considerable overlap between this constellation of symptoms and those of gastroesophageal reflux disease (GERD), biliary tract disease, irritable bowel syndrome, and chronic pancreatitis. This condition is reported in approximately 25% of the population each year, but most do not seek medical care (27,28).

TABLE 17.3 Classification of nonulcer dyspepsia by symptom type and their treatments

Classification	Symptoms	Treatment
Reflux-like	Heartburn and regurgitation without esophagitis	Antacid, H₂-blocker, and proton pump inhibitor
Ulcer-like	Epigastric pain relieved by food and antacids, relapse, and remission, without ulcer	As above
Dysmotility-like	Abdominal bloating, distension, early satiety, nausea, and vomiting	Prokinetic agent and antiflatulence agent
Nonspecific	Symptoms do not fall into one of the three categories in the preceding text	Start simple: antacid and antiflatulence agent (simethicone)

Pathophysiology/Etiology

Results of upper GI endoscopy in 3,667 general medical patients with dyspepsia were as follows: normal (34%), gastroesophageal reflux (24%), inflammation (20%), ulcer (20%), and cancer (2%) (27). Dyspepsia is divided into two categories: organic dyspepsia and functional dyspepsia. Patients in the first group have anatomical abnormalities (e.g., peptic ulcer disease, GERD, or gastric or esophageal cancer). Patients in the second category have symptoms for which no focal lesion can be found (Table 17.3). Recent studies have shown potential associations between specific pathophysiologic disturbances and functional dyspeptic symptoms. Delayed gastric emptying reported in approximately 30% of patients with functional dyspepsia is associated with postprandial fullness, nausea, and vomiting. Impaired gastric accommodation present in 40% of patients with functional dyspepsia is found to be associated with early satiety. Hypersensitivity to gastric distension is observed in 37% of patients with functional dyspepsia and is associated with postprandial pain, belching, and weight loss. Psychosocial factors have also been identified as pathophysiologic mechanisms (29,30).

Dysmotility-like dyspepsia, or gastroparesis, is commonly seen in patients with cancer due to autonomic nervous system dysfunction or use of anticholinergic drugs or opioids. It is associated with symptoms like bloating, abdominal distension, flatulence, and prominent nausea. Patients with this condition tend to have premature satiety with resultant epigastric heaviness or fullness even after the consumption of small meals (31). The diagnosis of paraneoplastic dyspepsia requires a high index of clinical suspicion.
A panel of serologic tests for paraneoplastic autoantibodies, scintigraphic gastric emptying, and esophageal manometry are useful as first-line screening tests. Nuclear scintigraphy is considered the gold standard for diagnosing and quantifying delayed gastric emptying. Seropositivity for type 1 antineuronal nuclear antibody, Purkinje cell cytoplasmic antibody, or N-type calcium channel-binding antibodies has been detected in patients with paraneoplastic gastroparesis, but its diagnostic value is under investigation (32).

Recent studies have linked gastroparesis to disruption of the interstitial cells of Cajal (ICC). These are fibroblast like cells, which have been identified in the gut by electron microscopy and by immunohistochemistry for Kit protein. By generating electrical slow waves, the ICC are intercalated between the intramural neurons and the effector smooth muscular cells to form a gastroenteric pacemaker system. It has been recently found that the loss of ICC causes dysmotilitylike symptoms in vivo. A loss of these cells has been detected in patients with paraneoplastic gastroparesis (33).

Other causes of cancer-induced dyspepsia include gastric cancer or lymphoma, gastritis secondary to radiotherapy/chemotherapy, gastric compression secondary to intraabdominal tumor, hepatomegaly, splenomegaly, ascites, or gastric outlet obstruction due to tumor. Medications that have been associated with dyspepsia include acarbose, alcohol, alendronate, codeine, iron, metformin, nonsteroidal anti-inflammatory drugs, erythromycin, potassium, corticosteroids, and theophylline. Dosage reduction or discontinuation of the offending agent may relieve dyspepsia.

Management/Treatment

The management of organic dyspepsia should be directed at the cause. Treatment maybe based on previous history (e.g., obstructing lesion responding to primary tumor treatment) or recent endoscopy findings. In functional dyspepsia, treatment should be based on symptoms (Table 17.3). Nutrition support in gastroparesis begins with encouraging smaller volume, low-fat, low-fiber meals and, if necessary, liquid caloric supplements. Metoclopramide is now the prokinetic drug of choice (34). Controlled-release metoclopramide (20 to 80 mg q12h) is effective in ameliorating symptoms of the cancer-induced dyspepsia such as nausea, vomiting, loss of appetite, and bloating (35).

Moreover, subcutaneous administration of metoclopramide is an important method, allowing for continued guaranteed absorption. Low-dosage erythromycin also has a prokinetic role, either alone or in combination with metoclopramide. Domperidone, a centrally acting antiemetic and prokinetic, is not available in US markets. Antiemetics should be used for nausea, which is a very severe debilitating symptom. There should be a low threshold for placing a jejunal feeding tube either by laparoscopy or by mini-laparotomy. Parenteral nutrition should be used only briefly during hospitalization and not encouraged or sustained in an outpatient. Most excitingly, the era of gastric electrical stimulation has arrived for patients not responding to standard medical therapy. The dramatic decrease in nausea and vomiting, as well as a sustained evidence of improved quality of life, gastric emptying, nutritional status, and decreased hospitalizations by this device, is documented by a long-term follow-up of more than a year (36). Gastric pacemaker has been studied in patients with diabetes-induced gastroparesis but not in cancer. Further research is needed in patients with cancerinduced gastroparesis (37,38).

HEARTBURN

Definition/Incidence

Heartburn is the most common GI complaint in the western population; 33% to 44% of the population complain of heartburn at least monthly and 7% to 13% may have it daily (39). Heartburn is a retrosternal burning sensation that usually radiates proximally from the xiphoid process to the neck. It is caused by the reflux of the gastric content into the esophagus. GERD occurs when the amount of gastric content that refluxes into the esophagus exceeds the normal limit, causing symptoms with or without esophagitis. Although there is no clear evidence that GERD is more common in those with cancer, certain conditions in this population may increase their risk, such as intra-abdominal lesions, which increase pressure on the stomach. In addition to the typical symptoms (heartburn, regurgitation, and dysphagia), abnormal reflux can cause atypical symptoms such as coughing, chest pain, and wheezing and also damage to the lungs (pneumonia, asthma, and idiopathic pulmonary fibrosis), vocal cords (laryngitis and cancer), ear (otitis media), and teeth (enamel decay). Approximately 50% of the patients with reflux develop esophagitis, which is classified on the basis of severity.

Pathophysiology/Etiology

The most important pathophysiologic factor in GERD is frequent transient relaxation of the lower esophageal sphincter (LES). Other factors include anatomic disruption of the LES as in hiatal hernia, transient increase in intra-abdominal pressure, abnormal esophageal peristalsis with impaired clearance of acid, and gastroparesis.

A number of foods, drugs, and neurohumoral factors reduce basal LES pressure, making patients prone to gastroesophageal reflux and heartburn (Table 17.4). Avoiding these foods and medications often constitutes the initial treatment of GERD. Some common agents that increase LES pressure include a protein meal, bethanechol, metoclopramide, and α-adrenergic agonists.

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